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. 2012 Jan;19(1):109-13.
doi: 10.1038/gt.2011.87. Epub 2011 Jun 16.

Coagulation factor X mediates adenovirus type 5 liver gene transfer in non-human primates (Microcebus murinus)

R Alba  1 , A C Bradshaw, N Mestre-Francés, J-M Verdier, D Henaff, A H Baker
Affiliations

Coagulation factor X mediates adenovirus type 5 liver gene transfer in non-human primates (Microcebus murinus)

R Alba et al. Gene Ther. 2012 Jan.

Abstract

Coagulation factor X (FX)-binding ablated adenovirus type 5 (Ad5) vectors have been genetically engineered to ablate the interaction with FX, resulting in substantially reduced hepatocyte transduction following intravenous administration in rodents. Here, we quantify viral genomes and gene transfer mediated by Ad5 and FX-binding-ablated Ad5 vectors in non-human primates. Ad5 vectors accumulated in and mediated gene transfer predominantly to the liver, whereas FX-binding-ablated vectors primarily targeted the spleen but showed negligible liver gene transfer. In addition, we show that Ad5 binding to hepatocytes may be due to the presence of heparan sulfate proteoglycans (HSPGs) on the cell membrane. Therefore, the Ad5-FX-HSPG pathway mediating liver gene transfer in rodents is also the mechanism underlying Ad5 hepatocyte transduction in Microcebus murinus.

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Figures

Figure 1
Figure 1. Biodistribution of Ad5CMVlacZ and FX-binding ablated Ad5CMVlacZ-HVR5*7*E451Q vectors at 48 hours
Viral genome accumulation was measured in different tissues after the administration of 1×1011 vp of control and FX-binding ablated Ad5 vectors in non-human primates (Microcebus murinus). Viral genomes were quantified from 100 ng of purified DNA and analyzed by SYBR green qPCR. Statistics were performed with natural log values using one way ANOVA (*<0.05 Vs Ad5CMVlacZ, n=5).
Figure 2
Figure 2. Transduction profiles of Ad5CMVlacZ and FX-binding ablated Ad5CMVlacZ-HVR5*7*E451Q vectors at late time points (48h)
β-galactosidase protein expressed from viral vectors was quantified using the βgal ELISA assay (Roche, UK) from non-human primate (Microcebus murinus) samples following the intravenous injection of 1×1011 vp/animal. Statistics were performed with natural log values using one way ANOVA (*<0.05 Vs Ad5CMVlacZ, n=5).
Figure 3
Figure 3. β-galactosidase visualization by immunohistochemical studies
β-gal expression in liver and spleen sections from non-human primates (Microcebus murinus) was analyzed by immunohistochemistry after the intravascular administration of 1×1011 vp of Ad5CMVlacZ and FX-binding ablated Ad5CMVlacZ-HVR5*7*E451Q at low magnification (40X).
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